The mononuclear phagocyte system is an important element in the host's defenses against neoplasia but is not always effective, as the host is not always able to concentrate and appropriately modulate mononuclear phagocytes at sites of neoplastic cells. The effective accumulation of mononuclear phagocytes within tumors and their activation for cytolytic function are controlled by a complex interplay of signals from host, environment, and tumor. Murine macrophages develop activation by interacting with multiple signals and by passing through stages characterized by objective markers. The specific molecular signals that induce activation and regulate the activated state are being defined. In particular, murine and human neoplasms contain and release low molecular weight factors, reactive with monoclonal antibodies against the retrovirus envelope protein P15E, that inhibit the chemotaxis and accumulation of mononuclear phagocytes. We hypothesize that the complex activation path usually seen can be altered or deranged in tumor-bearing hosts, perhaps by such low molecular weight factors. Several areas are currently emphasized and studied: (1)\The definition in molecular terms of low molecular weight inhibitors. Numerous lines of evidence suggest that these are products related to and/or coded for by retroviruses, particularly retroviral envelope proteins such as P15E. An exciting finding in this area has been that a wide variety of human and murine lines contain these low molecular weight inhibitors and that these inhibitors are active in vivo. (2)\The mechanisms of recognition of kill by human monocytes. (3)\The regulation of activation at the molecular level. We have found evidence that one of the major steps in development and activation, the complex chain of events set in motion by gamma interferon, is mediated and regulated by protein kinase-C. (4)\The role of macrophages present in tumors in vivo. We have found that, in tumors undergoing immune-mediated attack induced by systemic administration of antibodies of the IG2a isotope, macrophages activated for a novel type of antibody-dependent kill are intimately involved. Studies will focus on: (1)\furthering progress in understanding the relationship of retroviruses oncogenes they encode and production of low molecular weight factors; (2)\the mechanisms used by human monocytes for recognition in kill; (3)\how signals from the gamma interferon receptor to protein kinase-C are transmitted; and (4)\the role of macrophages in rejection of tumors in vivo when such a rejection is not induced by antibodies. (MB)